Esters of retinoic acid

ABSTRACT

Esters and amides of all-trans-retinoic acid are disclosed which are useful for their ultraviolet (UV) absorption properties.

BACKGROUND OF THE INVENTION

Retinoic acid is known to be useful for the treatment of acne. See, forexample, U.S. Pat. No. 3,729,568, which discloses the use of retinoicacid compositions for the treatment of acne. While retinoic acid is alsoknown to have ultraviolet (UV) absorption properties, it is not usefulas a sunscreen agent for skin application because of its irritatingeffects on human skin in effective sunscreening amounts, as well asother metabolic effects. Although these effects are useful in thetreatment of acne, they negate the usefulness of retinoic acid as ahuman sunscreening agent. Surprisingly, of the 48 novel esters andamides of all-trans-retinoic acid which we have prepared, 41 have beenfound to be non-irritating to human skin and to be substantially free ofthe metabolic effects characteristic of retinoic acid. The other sevencompounds, which are useful for the treatment of acne, are the subjectof our U.S. Pat. No. 4,055,659 entitled "Retinoic Acid Derivatives."

SUMMARY OF THE INVENTION

This invention relates to novel esters and amides of all-trans-retinoicacid which are non-irritating to human skin and are substantially freeof the metabolic effects characteristic of retinoic acid. Moreparticularly, the present invention relates to:

(A) novel esters of all-trans-retinoic acid having the followingformula: ##STR1## wherein X is a member selected from the groupconsisting of: ##STR2## 2-cyclohexylethyl; 10-carbomethoxydecyl;4-hydroxybutyl; cholesteryl; mixed m- and p-vinylbenzyl; and4-bromobenzyl;

(B) novel esters of all-trans-retinoic acid having the followingformula: ##STR3## wherein Y is a member selected from the groupconsisting of: cholesteryloxy; phenyl; 4-bromophenyl; 4-methoxyphenyl;4-nitrophenyl; 4-hydroxyphenyl; 4-methylphenyl; 4-cyanophenyl;4-ethoxyphenyl; 4-acetoxyphenyl; 2-naphthyl; 4-biphenyl;2,5-dimethoxyphenyl; 2,4-dichlorophenyl; 2,4-dimethylphenyl;3,4-diacetoxyphenyl; 3,4,5-trimethoxyphenyl; and 2,4,6-trimethylphenyl;and

(C) novel amides of all-trans-retinoic acid having the followingformula: ##STR4## wherein Z is a member selected from the groupconsisting of: n-propylamino; tert-butylamino;1,1,3,3-tetramethylbutylamino; 1-morpholino; 4-hydroxylphenylamino;4-carbomethoxy-2-hydroxyphenylamino; β-(3,4-dimethoxyphenyl)-ethylamino;2-benzothiazolylamino; 1-imidazolyl; 1-(2-nicotinoylhydrazolyl);1-benzotriazolyl; 1-(1,2,4-triazolyl); ##STR5##

It has surprisingly been discovered that the retinoic acid derivativesof the invention, while possessing very good ultraviolet lightabsorption properties, do not have irritating effects on the skin andare substantially free of the metabolic effects which are characteristicof retinoic acid and, therefore, are useful as human sunscreen agents.That the compounds of the invention are substantially free of themetabolic effects characteristic of retinoic acid is demonstrated bytheir inactivity in the following test measuring DNA synthesis in whichretinoic acid is significantly active at greater than 95% confidencelevel. Further, the present compounds generally do not produce theexcessive erythema characteristic of retinoic acid.

Ten male guinea pigs (Hartley strain) weighing ca. 400 g. each were usedfor each compound to be tested. The animals were housed singly in wirecages, handled daily during experimentation, provided chow and water adlibitum, and maintained on 12/12 hour light/dark cycles. Prior to theexperimental procedure, the animals were maintained as just describedfor 3 days.

On the first day of the test, one ear (dorsal skin) of each animal wasrandomly selected and treated with 0.025 ml. of the experimentalsolution, and the other ear was treated with an equal volume of theplacebo vehicle (control). Ten animals for each compound were sotreated. These topical applications were made at 9:00 a.m. on the first4 days of the experiment. All the animals received chronicadministration of tritiated thymidine (³ H-TdR) for these first 4 days.The ³ H-TdR was given intraperitoneally at about 9:30 a.m., 1:30 p.m.,and 5:00 p.m. of each day (10 micro Curie in 0.1 ml. H₂ O/injection;specific activity = 2.0 Curie/millimole). On the 5th day (9:00 a.m.),the animals were killed, and 6 mm. diameter punches of ear skin from thecentral portion of the treated sites were harvested.

Each of these tissue samples was solubilized at 37°-50° C. for 13 daysin 1 ml. of an alkali solubilizer sold by Amersham-Searle Co. under theregistered trademark "NCS" Solubilizer. The dissolved tissues kept innylon scintillation vials were acidified with 0.025-0.050 ml. of aceticacid, and diphenyloxazole in toluene was added as a fluor to detect thebeta particles emitted by absorbed tritiated thymidine. Theradioactivity of the samples was determined by multiple counting on aBeckman LS Counter. All count per minute values were quench corrected byexternal standardization to yield disintegrations per minute (dpm)/6mm.punch of skin. Quench correction is especially important as some of thesamples show faint yellow coloration due to presence of the retinylderivatives, and therefore present considerable color quench.

The test compounds were found to be inactive (confidence level less than90%) in the above test at up to 0.2% concentration by weight whenapplied in 50:50 parts by weight propylene glycol-ethanol or 35:35:30parts by weight propylene glycol-ethanol-chloroform.

The subject compounds strongly absorb ultraviolet (UV) light, generallyabove 280 nm., and are useful as UV-screening materials, for example, inplastic products and sunburn preventive formulations. They may be usedas UV-absorbers in plastics and resins such as, for example,polystyrene, polyethylene, polypropylene, polyacrylics (e.g.,methacrylate resins, polyacrylamides, polyacrylonitrile fibers, etc.),polyamide (e.g., nylon) fibers, and polyester fibers. The inclusion ofabout 0.01-5.0 percent of the absorber, based on the polymer weight, isusually sufficient to render protection against UV light, such as inplastic films, light filters, etc. The absorber may be incorporated intothe mixture of monomers before polymerization to form the polymer or itmay be incorporated into the polymer at other stages during itshandling, as by milling into the polymer together with other compoundingingredients, or during the spinning of the polymer into fibers, etc. Thecompounds are preferably employed as sunscreening agents in typicalanti-sunburn formulations in amounts of about 0.5-10 percent by weight(see G. W. van Ham & W. P. Herzog, Chapter 6, "The Design of SunscreenPreparations," in "Drug Design IV," E. J. Ariens, Ed., Academic Press,N.Y. and London 1973).

The compounds of the invention may be prepared by one of the followingmethods:

(A) In the first method of preparation, all-trans-retinoic acid or analkali metal salt of all-trans-retinoic acid is reacted with anappropriate alkyl halide. This reaction is conducted in an appropriateinert organic solvent, such as for example an ether (e.g., diethylether,tetrahydrofuran, and the like), an ester such as ethyl acetate, or thelike. The desired product may be isolated and purified by methods knownin the art.

(B) In the second method, all-trans-retinoyl chloride is reacted with anappropriate amine or alcohol to form the desired ester or amide. Thealcohol or amine is preferably present in a slight molar excess, and thereaction may be conducted in an appropriate inert organic solvent suchas for example an aromatic hydrocarbon (e.g., benzene, toluene, xylene,and the like), a halogenated hydrocarbon (e.g., chloroform, carbontetrachloride and the like), and the like.

(C) The hydrazone compounds of the invention are prepared by refluxingall-trans-retinoyl hydrazide with the appropriate ketone in a loweralkanol solution. The solution preferably also can contain a trace ofpyridine.

(D) The imide compounds of the invention may be prepared by reactingall-trans-retinoyl chloride with the appropriate N-hydroxyimide in anappropriate inert organic solvent such as for example an aromatichydrocarbon (e.g., benzene, toluene, xylene, or the like), a tertiaryamide such as N,N-dimethylformamide, and the like.

The desired products may be isolated and purified by methods known inthe art. The preparation of the compounds of this invention isillustrated by the following examples.

EXAMPLE I 10-Carbomethoxydecyl all-trans-Retinoate

The following were stirred together at 65° C. in a nitrogen atmospherefor 24 hours: powdered potassium all-trans-retinoate (3.38 g.; 0.010mole); powdered potassium iodide (1.66 g.; 0.010 mole); methyl11-bromoundecanoate (4.20 g.; 0.0150 mole); dry tetrahydrofuran, 30 ml.The reaction mixture was filtered with suction through sintered glass,and the filtrate was evaporated to give a thick red liquid. The liquidwas dissolved in 100 ml. of 95:5 petroleum ether-benzene and put on achromatographic column of 40-140 mesh silica gel. The column was elutedwith 50:50 petroleum ether-benzene. Fractions containing a mixture ofretinoate ester and unreacted bromoester were collected and evaporatedto give a yellow oil from which the retinoate crystallized when cooledand seeded. The crude crystals were suction filtered from unreactedbromoester. One recrystallization from 12.5 ml. of methanol yielded theretinoate ester, melting point 53°-55° C.; which showed the correctproton magnetic resonance spectrum and elemental analysis. Anal. Calcd.for C₃₂ H₅₀ O₄ : C, 77.1; H, 10.1. Found: C, 76.7; H, 10.1.

EXAMPLE II Cholesteryl all-trans-Retinoate

A solution of retinoyl chloride was prepared from 3.0 g. ofall-trans-retinoic acid and 0.92 g. of phosphorous trichloride in 20 ml.of benzene. This solution was added during 18 minutes to 3.48 g. ofcholesterol and 28 ml. of N,N-dimethylaniline with stirring and heatingto 90° C. in an open-neck flask. Stirring was continued for anadditional 40 minutes, during which most of the benzene evaporated. Thereaction mix was dissolved in 300 ml. of ethyl ether, and the ethersolution was successively extracted with three 50-ml. portions of cold 2N sulfuric acid, two 50-ml. portions of cold saturated sodiumbicarbonate solution, and four 50-ml. portions of cold water. Crystalsformed in the ether solution as it stood in the refrigerator overnight.They were twice recrystallized from 50:50 chloroform-ethanol (20 ml. pergram), giving pure product, melting point 162°-163° C. The protonmagnetic resonance spectrum was consistent with the structure. Anal.Calcd. for C₄₇ H₇₂ O₂ : C, 84.4; H, 10.8. Found: C, 84.5; H, 10.8.

EXAMPLE III N,N'-Dicyclohexyl-N-(all-trans-Retinoyl)-Urea

The following were magnetically stirred in a 50-ml. flask at roomtemperature for 48 hours: 3.00 g. of all-trans-retinoic acid, 2.06 g. ofN,N'-dicyclohexylcarbodiimide, 1.01 g. of triethylamine, 15 ml. of drytetrahydrofuran. The solid in the reaction mixture was filtered off andwashed with 20 ml. of tetrahydrofuran. Evaporation of thetetrahydrofuran filtrate plus washings left a yellow, pasty solid whichwas then diluted with 150 ml. of ethyl ether. The ether was washed with25 ml. of cold 5% hydrochloric acid, with 25 ml. of cold saturatedpotassium bicarbonate, and finally with four successive 25-ml. portionsof ice water. During the washing procedure, a finely divided solidseparated from the ether. It was crystallized from 112 ml. of acetone.The crystals melted at 171°-172° C. The proton magnetic resonancespectrum confirmed the structure of the compound. Anal. Calcd. for C₃₃H₅₀ N₂ O₂ : C, 78.2; H, 9.94; N, 5.53. Found: C, 78.2; H, 10.2; N, 5.43.

EXAMPLE IV Trans-β-Ionone (All-trans-Retinoyl)-Hydrazone

A solution of retinoyl chloride was prepared from 3.0 g. ofall-trans-retinoic acid and 0.92 g. of phosphorous trichloride in 50 ml.of benzene by stirring at room temperature for 2.2 hours. This solutionwas added dropwise to a stirred solution of 4.80 g. of dry hydrazine in20 ml. of anhydrous ethyl ether during 30 minutes while cooling in anice bath. Stirring was continued for 3 hours at room temperature, thenfor an additional hour at 50°-60° C. The reaction mixture was dilutedwith 150 ml. of ethyl ether, then extracted with four 25-ml. portions ofice water. After drying over sodium sulfate, the ether solution wasevaporated leaving crude all-trans-retinoyl hydrazide.

The hydrazide was dissolved in 15 ml. of 95% ethanol, and to thesolution was added 7.68 g. of trans-β-ionone in 15 ml. of 95% ethanoland one drop of pyridine. The solution was refluxed for 15 minutes,filtered, and cooled in ice, causing precipitation of yellow crystals.These crystals were recrystallized from 1:8 chloroform-ethanol (22.5 ml.per gram), giving pure product, melting point 183°-185° C., whichexhibited the correct proton magnetic resonance spectrum. Anal. Calcd.for C₃₃ H₄₈ N₂ O: C, 81.1; H, 9.90; N, 5.73. Found: C, 81.1; H, 10.0; N,5.51.

EXAMPLE V N-(All-trans-Retinoyloxy)-Succinimide

A solution of retinoyl chloride was prepared by magnetically stirring3.00 g. of all-trans-retinoic acid and 0.92 g. of phosphoroustrichloride for two hours in 50 ml. of dry benzene at room temperature.This solution was added dropwise during 30 minutes at room temperatureto a stirred solution of 5.75 g. of N-hydroxysuccinimide dissolved in 10ml. of dry N,N-dimethylformamide. The reaction mixture was stirred for1.5 hours longer, then immersed in an 80° C. oil bath for 15 minutes.The reaction mixture was diluted with 150 ml. ethyl ether, and the thickred oil which did not dissolve was discarded. The ether solution waswashed with five 30-ml. portions of ice water and dried over sodiumsulfate. Evaporation of the solvents left a yellow powder which wasrecrystallized twice from 1:2 chloroform-n-hexane (7.5 ml. per gram) andonce from isopropanol (25 ml. per gram). Product melting point was177°-179° C. The proton magnetic resonance spectrum was consistent withthe structure. Anal. Calcd. for C.sub. 24 H₃₁ NO₄ : C, 72.5; H, 7.86; N,3.52. Found: C, 72.5; H, 7.91; N, 3.50.

EXAMPLE VI 2-Cyclohexylethyl all-trans-Retinoate

The following were refluxed in an aluminum foil-covered flask undernitrogen for 28 hours: 5.0 g. of all-trans-retinoic acid; 3.5 g. ofcyclohexylethyl bromide; 15.0 g. of anhydrous potassium carbonate; 0.05g. of potassium iodide; 0.05 g. of p-methoxyphenyl; and 50 ml. oftetrahydrofuran. The reaction mixture was then diluted with 200 ml. ofn-hexane and filtered through a one-half-inch-thick pad of alumina. Thepad was eluted with 100 ml. of 1:1 benzene-n-hexane and the washingswere combined with the original filtrate. The solvents were removed on arotary evaporater, and the residual yellow oil was placed on a silicagel column (100 g.) with 20 ml. of n-hexane. The column was eluted with600 ml. of 1:1 benzene-n-hexane. The first 200 ml. of eluted solutionwere discarded; the next 300 ml. were collected, and the solvent wasevaporated. The yellow oil residue was evacuated for two days at apressure of 0.03 mm. and room temperature. The proton magnetic resonancespectrum of the resulting oil was consistent with the structure. Anal.Calcd. for C₂₈ H₄₂ O₂ : C, 81.9; H, 10.3. Found: C, 81.8; H, 10.3.

EXAMPLE VII 4-Hydroxybutyl all-trans-Retinoate

A solution of retinoyl chloride was prepared by stirring 3.0 g. ofall-trans-acid and 0.92 g. of phosphorous trichloride in 25 ml. of drybenzene for about 2 hours. A solution of 6.0 ml. of 1,4-butanediol and8.0 ml. of pyridine was stirred magnetically, cooled to 4° C., and theretinoyl chloride solution was added during 5 minutes. The reactionmixture was stirred at 20° C. for 50 minutes, and then at 43° C. for 15minutes, all under a nitrogen atmosphere. The lightamber reactionmixture was diluted with 20 ml. of ethyl ether. The resulting solutionwas washed with two 20-ml. portions of 5 percent hydrochloric acid, 20ml. of cold 10 percent sodium bicarbonate solution, and 20 ml. of coldbrine solution. The washed ether solution was then dried over magnesiumsulfate.

The washed and dried solution was placed on 80 ml. of alumina and elutedsuccessively with 200 ml. of ethyl ether and 600 ml. of ethyl acetate.Crude product was concentrated from the ethyl acetate eluate and againplaced on alumina (75 ml.) with the aid of 20 ml. of ethyl ether. Theproduct was eluted from the alumina with 1,400 ml. of ethyl ether.Composition of the fractions was monitored by thin-layer chromatography.The appropriate fractions were combined, the ether evaporated, and theresidual viscous yellow oil was evacuated at a pressure of 0.005 mm. for24 hours. The proton magnetic resonance spectrum of the product wasconsistent with the structure. Anal. Calcd. for C₂₄ H₃₆ O₃ : C, 77.4; H,9.74. Found: C, 77.1; H, 9.96.

EXAMPLE VIII All-trans-Retinoyloxyacetyl-3,4,5-Trimethoxybenzene

Potassium retinoate was made by neutralizing 3.00 g. ofall-trans-retinoic acid in 30 ml. of tetrahydrofuran with 15.6 ml. of0.640 N methanolic potassium hydroxide. The solvent was evaporated in arotary evaporator, and the residue was dried at a pressure of less than0.5 mm. for several hours.

Powdered potassium retinoate (3.03 g.) in 20 ml. ofhexamethylphosphoramide was stirred overnight at room temperature with2.89 g. of 2-bromo-3',4',5'-trimethoxyacetophenone. The turbid yellowreaction mixture was poured into 30 ml. of cold 5% hydrochloric acid,precipitating a sticky yellow solid. The solid hardened when washed bydecantation with 60 ml. of cold water. The solid was dissolved in 200ml. ethyl ether, and the ether solution was washed with five 25-ml.portions of cold water. After drying over sodium sulfate, the ethersolution was evaporated leaving a yellow powder.

The powder was recrystallized twice from 1:2 chloroform-methanol (7.5ml. per gram), giving yellow crystals, melting point 123.0°-123.5° C.The proton magnetic resonance spectrum of the product was consistentwith the structure. Anal. Calcd. for C₃₁ H₄₀ O₆ : C, 73.2; H, 7.93.Found: C, 73.3; H, 7.93.

EXAMPLE IX 4-(All-trans-Retinoyl)-Aminophenol

A solution of retinoyl chloride was prepared by magnetically stirring3.00 g. of all-trans-retinoic acid and 0.92 g. of phosphoroustrichloride for 2.25 hours in 50 ml. of dry benzene. During 21 minutes,the retinoyl chloride solution was then added to a solution of 5.46 g.of 4-aminophenol in 16 ml. of anhydrous N,N-dimethylformamide and 2 ml.of anhydrous ethyl ether, while stirring under a nitrogen atmosphere andcooling in an ice bath. Stirring was then continued for 3 hours at roomtemperature and for an hour more at 50° C.

The reaction mixture was diluted with 150 ml. of ethyl ether. The ethersolution was extracted with two 25-ml. portions of cold 5% hydrochloricacid and then was washed with four 25-ml. portions of cold water. Afterthe washed solution was dried over sodium sulfate, the solvent wasevaporated, leaving a dark-yellow solid. The solid was recrystallizedfirst from methanol (6 ml. per gram), then from 1:1.7chloroform-n-hexane (8 ml. per gram). The product had a melting point of159°-160° C. The proton magnetic resonance spectrum of the product wasconsistent with the structure with no extraneous resonances. Anal.Calcd. for C₂₆ H₃₃ NO₂ : C, 79.8; H, 8.49; N, 3.58. Found: C, 79.5; H,8.67; N, 3.56.

EXAMPLE X

Following the method of Example IV, but substituting an equivalentamount of acetone for the trans-β-ionone used therein, there is preparedacetone (all-trans-retinoyl)-hydrazone; m.p. 174°-175° C.

EXAMPLE XI

Following the method of Example V, but substituting an equivalent amountof N-hydroxyphthalimide for the N-hydroxysuccinimide used therein, thereis prepared N-(all-trans-retinoyloxy)-phthalimide; m.p. 177°-178° C.

EXAMPLE XII

Following the method of Example VIII, but substituting an equivalentamount of the appropriate halogen-containing compound for the2-bromo-3',4',5'-trimethoxyacetophenone used therein, the following areprepared:

    ______________________________________                                               Compound            m.p. (° C.)                                 ______________________________________                                        Cholesteryl all-trans-Retinoyloxyacetate                                                                 104-106                                            Mixed m- and p-vinylbenzyl all-trans-                                         Retinoates                 Liquid                                             4-Bromobenzyl all-trans-Retinoate                                                                        70.0-70.5                                          all-trans-Retinoyloxyacetylbenzene                                                                       132-133                                            4-(all-trans-Retinoyloxyacetyl)-bromobenzene                                                             136-137                                            4-(all-trans-Retinoyloxyacetyl)-                                              methoxybenzene             126-127                                            4-(all-trans-Retinoyloxyacetyl)-                                              nitrobenzene               151-152                                            4-(all-trans-Retinoyloxyacetyl)-phenol                                                                   180-181                                            4-(all-trans-Restinoyloxyacetyl)-toluene                                                                 125-126                                            4-(all-trans-Retinoyloxyacetyl)-benzo-                                        nitrile                    178-179                                            4-(all-trans-Retinoyloxyacetyl)-ethoxy-                                       benzene                    124.5-125.5                                        4-(all-trans-Retinoyloxyacetyl)-                                              acetoxybenzene             132-133                                            2-(all-trans-Retinoyloxyacetyl)-naphthalene                                                              120-121                                            4-(all-trans-Retinoyloxyacetyl)-biphenyl                                                                 142-143                                            all-trans-Retinoyloxyacetyl-2,5-dimethoxy-                                    benzene                    98-99                                              all-trans-Retinoyloxyacetyl-2,4-dichloro-                                     benzene                    106-107                                            all-trans-Retinoyloxyacetyl-2,4-dimethyl-                                     benzene                    117.5-118.5                                        all-trans-Retinoyloxyacetyl-3,4-diacetoxy-                                    benzene                    123-124                                            all-trans-Retinoyloxyacetyl-2,4,6-tri-                                        methylbenzene              116-117                                            ______________________________________                                    

EXAMPLE XIII

Following the method of Example IX, but substituting an equivalentamount of the appropriate amine for the 4-aminophenol used therein, thefollowing are prepared:

    ______________________________________                                        Compound                   m.p. (° C.)                                 ______________________________________                                        N-n-Propyl all-trans-retinamide                                                                          113-115                                            N-Tert.-butyl all-trans-retinamide                                                                       139-141                                            N-(1,1,3,3-Tetramethyl)-butyl all-trans-                                      retinamide                 Glass                                              N-(all-trans-Retinoyl)-morpholine                                                                        82-84                                              Methyl 4-(all-trans-Retinoylamino)-                                           salicylate                 198-199                                            N-(all-trans-Retinoyl)-imidazole                                                                         113-115                                            1-Nicotinoyl-2-(all-trans-retinoyl)-hydrazine                                                            191-194                                            1-(all-trans-Retinoyl)-benzotriazole                                                                     140-141                                            1-(all-trans-Retinoyl)-1,2,4-triazole                                                                    141-142                                            N-[β-(3,4-Dimethoxyphenyl)ethyl]-all-trans-                              retinamide                 140-142                                            2-(all-trans-Retinoylamino)-benzothiazole                                                                219-221                                            ______________________________________                                    

The use of the compounds of the invention is illustrated by thefollowing example. All parts are by weight.

EXAMPLE XIV

The following ingredients are homogeneously mixed to produce aformulation useful as a human sunscreening cream for topical applicationto the skin:

    ______________________________________                                        Ingredient         Parts                                                      ______________________________________                                        Glyceryl Stearate  10.0                                                       Isopropyl Myristate                                                                              10.0                                                       Spermaceti         5.0                                                        Cetyl Alcohol      2.5                                                        Steareth-20        2.625                                                      Steareth-2         0.375                                                      Propylene Glycol   5.0                                                        Xanthan Gum        0.3                                                        Sorbic Acid        0.2                                                        Butylated Hydroxytoluene                                                                         0.05                                                       Active Ingredient  2.5                                                        Water              61.45                                                      ______________________________________                                    

The active ingredient is any of the compounds of the present invention.

What is claimed is:
 1. An ester of all-trans-retinoic acid selected fromthe group consisting of:(A) esters of all-trans-retinoic acid having thefollowing formula: ##STR6## wherein X is mixed m and p-vinylbenzyl; and(B) esters of all-trans-retinoic acid having the following formula:##STR7## wherein Y is a member selected from the group consisting of:4-methoxyphenyl; 4-hydroxyphenyl; 4-methylphenyl; 4-ethoxyphenyl;4-acetoxyphenyl; 2-naphthyl; 4-biphenyl; 2,5-dimethoxyphenyl;2,4-dimethylphenyl; 3,4-diacetoxyphenyl; 3,4,5-trimethoxyphenyl; and2,4,6-trimethylphenyl.
 2. Ester of all-trans-retinoic acid according toclaim 1 having the following formula: ##STR8## 3.4-(all-trans-retinoyloxyacetyl)-methoxybenzene according to claim
 1. 4.4-(all-trans-retinoyloxyacetyl)-toluene according to claim
 1. 5.4-(all-trans-retinoyloxyacetyl)-phenol according to claim
 1. 6.4-(all-trans-retinoyloxyacetyl)-acetoxybenzene according to claim
 1. 7.4-(all-trans-retinoyloxyacetyl)-ethoxybenzene according to claim 1.